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GNAQ and GNA11 mutant nonuveal melanoma: a subtype distinct from both cutaneous and uveal melanoma.

  • Livingstone, E1
  • Zaremba, A1
  • Horn, S1, 2
  • Ugurel, S1
  • Casalini, B3, 4
  • Schlaak, M5
  • Hassel, J C6
  • Herbst, R7
  • Utikal, J S8, 9
  • Weide, B10
  • Gutzmer, R11
  • Meier, F12
  • Koelsche, C13
  • Hadaschik, E1
  • Sucker, A1
  • Reis, H14
  • Merkelbach-Bruse, S15
  • Siewert, M1
  • Sahm, F3, 4
  • von Deimling, A3, 4
  • And 5 more
  • 1 Department of Dermatology, University Hospital Essen, University of Duisburg-Essen, Hufelandstr. 55, 45122, Essen, Germany. , (Germany)
  • 2 Medical Faculty of the University Leipzig, Rudolf-Schönheimer-Institute of Biochemistry, Johannisallee 30, 04103, Leipzig, Germany. , (Germany)
  • 3 Department of Neuropathology, University Hospital Heidelberg, Ruprecht-Karls-University Heidelberg, Heidelberg, Germany. , (Germany)
  • 4 Clinical Cooperation Unit Neuropathology and DKTK, DKFZ, Heidelberg, Germany. , (Germany)
  • 5 Department of Dermatology, LMU München, Frauenlobstraße 9-11, 80337, Munich, Germany. , (Germany)
  • 6 Department of Dermatology and National Center for Tumor Diseases, University Hospital Heidelberg, Im Neuenheimer Feld 460, 69120, Heidelberg, Germany. , (Germany)
  • 7 Department of Dermatology, Helios Klinikum Erfurt, Nordhäuserstr. 74, 99089, Erfurt, Germany. , (Germany)
  • 8 Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany. , (Germany)
  • 9 Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim, Germany. , (Germany)
  • 10 Department of Dermatology, University of Tübingen, Liebermeisterstraße 25, 72076, Tübingen, Germany. , (Germany)
  • 11 Department of Dermatology, Medizinische Hochschule Hannover, Carl-Neuberg-Straße 1, 30625, Hannover, Germany. , (Germany)
  • 12 Department of Dermatology, Carl-Gustav-Carus University Hospital, Fetscherstr. 74, 01307, Dresden, Germany. , (Germany)
  • 13 Department of General Pathology, University Hospital Heidelberg, Ruprecht-Karls-University Heidelberg, Heidelberg, Germany. , (Germany)
  • 14 Institute of Pathology, University Hospital Essen, University of Duisburg-Essen, Hufelandstr. 55, 45122, Essen, Germany. , (Germany)
  • 15 Institute of Pathology, University Hospital Cologne, Kerpener Str. 62, 50924, Cologne, Germany. , (Germany)
  • 16 Dermatological Sciences, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.
  • 17 German Cancer Consortium (DKTK), Heidelberg, Germany. , (Germany)
  • 18 Deptartment of Dermatology, University of Würzburg, Josef-Schneider-Str. 2, 97080, Würzburg, Germany. , (Germany)
  • 19 Dermatopathologie bei Mainz, Bahnhofstr. 2B, 55268, Nieder-Olm, Germany. , (Germany)
Published Article
British Journal of Dermatology
Wiley (Blackwell Publishing)
Publication Date
Nov 01, 2020
DOI: 10.1111/bjd.18947
PMID: 32064597


GNAQ and GNA11 mutant nonuveal melanoma represent a poorly characterized rare subgroup of melanoma with a gene mutation profile similar to uveal melanoma. To characterize these tumours in terms of clinical behaviour and genetic characteristics. Patients with nonuveal GNAQ/11 mutated melanoma were identified from the prospective multicentre tumour tissue registry ADOREG, Tissue Registry in Melanoma (TRIM) and additional cooperating skin cancer centres. Extensive data on patient, tumour and treatment characteristics were collected retrospectively. Targeted sequencing was used to determine tumour mutational burden. Immunohistochemistry staining was performed for programmed death-ligand 1 and BRCA1-associated protein (BAP)1. Existing whole-exome cutaneous and uveal melanoma data were analysed for mutation type and burden. We identified 18 patients with metastatic GNAQ/11 mutant nonuveal melanoma. Tumours had a lower tumour mutational burden and fewer ultraviolet signature mutations than cutaneous melanomas. In addition to GNAQ and GNA11 mutations (nine each), six splicing factor 3b subunit 1 (SF3B1), three eukaryotic translation initiation factor 1A X-linked (EIF1AX) and four BAP1 mutations were detected. In contrast to uveal melanoma, GNAQ/11 mutant nonuveal melanomas frequently metastasized lymphatically and concurrent EIF1AX, SF3B1 and BAP1 mutations showed no apparent association with patient prognosis. Objective response to immunotherapy was poor with only one partial response observed in 10 treated patients (10%). Our findings suggest that GNAQ/11 mutant nonuveal melanomas are a subtype of melanoma that is both clinically and genetically distinct from cutaneous and uveal melanoma. As they respond poorly to available treatment regimens, novel effective therapeutic approaches for affected patients are urgently needed. What is already known about this topic? The rare occurrence of GNAQ/11 mutations in nonuveal melanoma has been documented. GNAQ/11 mutant nonuveal melanomas also harbour genetic alterations in EIF1AX, SF3B1 and BAP1 that are of prognostic relevance in uveal melanoma. What does this study add? GNAQ/11 mutant nonuveal melanomas show metastatic spread reminiscent of cutaneous melanoma, but not uveal melanoma. GNAQ/11 mutant nonuveal melanomas have a low tumour mutational burden that is higher than uveal melanoma, but lower than cutaneous melanoma. What is the translational message? Primary GNAQ/11 mutant nonuveal melanomas are a subtype of melanoma that is clinically and genetically distinct from both cutaneous and uveal melanoma. As metastatic GNAQ/11 mutant nonuveal melanomas respond poorly to available systemic therapies, including immune checkpoint inhibition, novel therapeutic approaches for these tumours are urgently needed. Linked Comment: Rafei-Shamsabadi. Br J Dermatol 2020; 183:806-807. © 2020 The Authors. British Journal of Dermatology published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists.

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